Microneedle array applicator device and method of array application

ABSTRACT

An applicator device including a housing, an impactor for impacting a microneedle array and accelerating the microneedle array toward the target site, wherein the impactor is capable of moving along an arcuate path to move the microneedle array toward the target site. Also, an applicator device including a housing, a patch applicator pivotally supported by the housing, and a torsion spring. The patch applicator has a retaining portion and a patch contacting portion, and the patch contacting portion is capable of moving along a substantially arcuate path between a first position and a second position. The torsion spring is capable of biasing the patch applicator relative to the housing.

CROSS-REFERENCE TO RELATED APPLICATIONS

The application is a divisional of U.S. Ser. No. 11/993,137, filed Dec.19, 2007 (now U.S. Pat. No. 8,784,363), which is a national stage filingunder 35 U.S.C. 371 of PCT/US2006/024671, filed Jun. 23, 2006, whichclaims priority to U.S. Provisional Application Ser. No. 60/694,447,filed on Jun. 27, 2005, and U.S. Provisional Application Ser. No.60/746,298, filed on May 3, 2006, which are incorporated herein in theirentirety.

FIELD

The present invention relates to microneedle array applicators andmethods of application of microneedle arrays.

BACKGROUND

Only a limited number of molecules with demonstrated therapeutic valuecan be transported through the skin via unassisted or passivetransdermal drug delivery. The main barrier to transport of moleculesthrough the skin is the stratum corneum (the outermost layer of theskin)

Devices including arrays of relatively small structures, sometimesreferred to as microneedles or micro-pins, have been disclosed for usein connection with the delivery of therapeutic agents and othersubstances through the skin and other surfaces. The devices aretypically pressed against the skin in an effort to pierce the stratumcorneum such that the therapeutic agents and other substances can passthrough the stratum corneum and into the tissues below. Microneedles canbe delivered using a patch that carries the microneedle array, which canfacilitate delivery of therapeutic agents and other substances.

Microneedle arrays and patches can be deployed with an applicator devicecapable of being used a number of different times. The microneedlearrays and patches are generally used once and then discarded. Theapplicator devices can be repeatedly reloaded with new microneedlearrays and patches.

The present invention provides an alternative microneedle arrayapplicator device.

BRIEF SUMMARY

In a first aspect of the present invention, a microneedle arrayapplication device includes a housing and an impactor. The housing has askin-contacting face that defines an opening that can be positioned at atarget site. The impactor is capable of impacting a microneedle arrayand accelerating the microneedle array toward the target site. Theimpactor is further capable of moving along an arcuate path to move themicroneedle array toward the target site.

In another aspect of the present invention, a microneedle arrayapplication device includes a housing having a surface-contacting facewith an opening and a drive member having a length extending from afixed end attached to the housing to a movable end. The drive member isbendable along its length and the movable end of the drive member isconfigured so as to be able to contact and propel a microneedle array.In one embodiment, the drive member comprises a leaf spring.

In another aspect of the present invention, an applicator deviceincludes a housing, an impactor pivotally supported by the housing, anda torsion spring. The impactor has an impacting portion that is capableof moving along a substantially arcuate path between a first positionand a second position. The torsion spring is capable of biasing theimpactor relative to the housing.

In another aspect of the present invention, a microneedle applicationdevice includes a housing having a skin-contacting face. A recess isdefined along the skin-contacting face of the housing, and the recesshas a bottom portion. An opening is defined in the bottom portion of therecess, and the opening can be positioned over a target site. At leastone retaining surface is disposed along the bottom portion of the recessand adjacent to the opening, for holding a patch carrying a microneedlearray prior to application at the target site. The retaining surface isgenerally parallel to the bottom portion of the recess, and themicroneedle array can be aligned below the opening.

In another aspect of the present invention, a microneedle arrayapplication device includes a housing and an impactor. The housing has askin-contacting face that defines an opening that can be positioned at atarget site. The impactor is capable of impacting a microneedle arrayand accelerating the microneedle array toward the target site. Theimpactor comprises a magnet suitable for releasably retaining a magneticmicroneedle patch.

In another aspect of the present invention, a method of microneedlearray application includes providing a microneedle application devicecapable of accelerating a microneedle array toward a target site,mounting the microneedle array on the microneedle array applicationdevice, and moving the microneedle array toward the target site along asubstantially arcuate path.

In another aspect of the present invention, a method of microneedlearray application includes providing a microneedle application devicecapable of bringing a microneedle array toward a target site, mountingthe microneedle array on the microneedle array application device, andmoving the impactor along a substantially arcuate path to bring themicroneedle array into contact with the target site.

The above summary is not intended to describe each disclosed embodimentor every implementation of the present invention. The figures and thedetailed description, which follow, more particularly exemplifyillustrative embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of an applicator device.

FIG. 2 is a perspective view of a portion of the applicator device ofFIG. 1.

FIG. 3 is a perspective view of a patch mounted on the applicator deviceof FIGS. 1 and 2.

FIG. 4 is a partial cross-sectional view of a microneedle cartridgemounted on the applicator device of FIGS. 1-3.

FIG. 5A is a detailed view the patch contacting surface of oneembodiment of an applicator device.

FIG. 5B is a detailed view the patch contacting surface of anotherembodiment of an applicator device.

FIG. 6A is a perspective view of another applicator device havingpeelable seals.

FIG. 6B is a perspective view of the applicator of FIG. 6A with thepeelable seals removed.

FIG. 6C is a cross-sectional view of the applicator of FIGS. 6A, B in aloaded position.

FIG. 6D is a cross-sectional view of the applicator of FIGS. 6A, B in apartially released position.

FIG. 6E is a cross-sectional view of the applicator of FIGS. 6A, B in aposition where a microneedle array can contact a target surface.

FIG. 6F is a cross-sectional view of the applicator of FIGS. 6A, B beingremoved from a microneedle array that has been deployed onto a targetsurface.

FIG. 7A is perspective top view of still another applicator device.

FIG. 7B is perspective bottom view of the applicator of FIG. 7A.

FIG. 7C is a cross-sectional view of the applicator of FIGS. 7A, B in aloaded position.

FIG. 7D is a cross-sectional view of the applicator of FIGS. 7A, B in aposition where a microneedle array can contact a target surface.

FIG. 7E is a cross-sectional view of the applicator of FIGS. 7A, B beingremoved from a microneedle array that has been deployed onto a targetsurface.

While the above-identified drawing figures set forth several embodimentsof the invention, other embodiments are also contemplated, as noted inthe discussion. In all cases, this disclosure presents the invention byway of representation and not limitation. It should be understood thatnumerous other modifications and embodiments can be devised by thoseskilled in the art, which fall within the scope and spirit of theprinciples of the invention. The figures may not be drawn to scale. Likereference numbers have been used throughout the figures to denote likeparts.

DETAILED DESCRIPTION

Microneedle arrays can be used for transdermal or intradermal deliveryof molecules, and in particular may have utility for the delivery oflarge molecules that are ordinarily difficult to deliver by passivetransdermal delivery. In some instances, the microneedle arrays may beapplied as part of a microneedle device which, for example, may be inthe form of a patch designed to adhere to skin and help keep the arrayin intimate contact with the skin. As used herein, “array” refers to themedical devices described herein that include one or more structurescapable of piercing the stratum corneum to facilitate the transdermaldelivery of therapeutic agents or the sampling of fluids through or tothe skin. “Microstructure,” “microneedle” or “microarray” refers to thespecific microscopic structures associated with the array that arecapable of piercing the stratum corneum to facilitate the transdermaldelivery of therapeutic agents or the sampling of fluids through theskin. By way of example, microstructures can include needle orneedle-like structures as well as other structures capable of piercingthe stratum corneum. Microneedle arrays can be deployed using anapplicator device that moves microneedle arrays into contact with atarget location, such as a location on a patient's skin.

FIG. 1 is a cross-sectional view of an applicator device 20 having ahousing 22 that includes a base 24 and an upper cover structure 26. Thebase 24 is generally rectangular in shape, and has a recess 28 locatedon a bottom face 30 thereof. A generally circular opening 32 is definedin the recess 28 of the base 24. A raised portion 34 is formed on anupper face 36 of the base 24 for holding a patch accelerating or patchapplicator assembly 38.

A mounting structure or retaining portion of the applicator device 20 isformed by a pair of retainers 40, also referred to as a first retainerand a second retainer, connected to the base 24 (only one retainer 40 isvisible in FIG. 1). The retainer members 40 are generally elongate andeach have a substantially flat upper surface 42 that is generallyparallel to and facing a bottom portion 44 of the recess 28, and isspaced from the bottom face 30 (i.e., the skin-contacting face) of thebase 24. The pair of retainer members 40 are located on opposite sidesof the opening 32 and are connected to the base 24 at one side of therecess 28. The retainer members 40 define an opening 46 at one end foraccepting patches between the retainer members 40 and the bottom portion44 of the recess 28. The upper surfaces 42 of the retainer members 40may be non-stick or release surfaces. A non-stick or release surface canbe achieved, for example, by a non-stick or release coating applied tothe upper surfaces 42. The non-stick or release coating can be selectedaccording to the desired use of the applicator device 20. For instance,a release coating, such as a low surface energy silicone, fluoropolymer,or fluoro-silicone release coating, can be selected based upon theadhesives used with patches applied using the patch application device20. In further embodiments, a blade or other cutting means can beprovided as part of the mounting structure, for separating portions ofitems from patches mounted on the applicator.

The upper cover structure 26 is connected to the base 24 at or near aperimeter of the base 24. The upper cover structure 26 is shaped to fiton the base 24, and defines a volume, which is selected to provide spacefor the patch accelerating assembly 38. In some embodiments, the housing22 may also provide space for storing patches (e.g., a roll of patches)for eventual deployment by the applicator device 20. A slot 48 isdefined in a side portion of the upper cover structure 26. In theembodiment shown in FIG. 1, the slot 48 is arcuate in shape andgenerally resembles a half circle, with the open portion of the halfcircle facing the base 24 of the housing 22.

Both the base 24 and the upper cover structure 26 can be formed of apolymer material.

FIG. 2 is a perspective view of a portion of the applicator device 20with the upper cover portion 26 omitted to show interior portions of thedevice 20. As shown in FIG. 2, the patch acceleration assembly 38includes a frame member 60, an impactor 62, a handle 64, a bracket 66,and a torsion spring 68. The torsion spring 68 serves as a drive memberto bias the impactor relative to the housing. The bracket 66 is mountedto the raised portion 34 of the base 24 of the housing 22 and pivotallyretains the frame member 60. In some instances the bracket 66 may bedirectly affixed to the base 24, for example, if the base has sufficientthickness to allow for placement of the torsion spring 68. The framemember 60 can be a wire formed as a rectangular loop. The impactor 62 isattached to the frame member 60 opposite the bracket 66, and is theportion of the patch acceleration assembly 38 that interfaces with apatch to move it (i.e., to accelerate it), that is, it is the patchcontacting portion of the device. The impactor 62 has a patch contactingsurface 70 that is configured according to characteristics of a desiredapplication, for instance, based upon the shape of a patch to beapplied. In the embodiment shown in FIG. 1, the patch contacting surface70 is configured so that it is generally parallel to and aligned withthe frame member 60. Furthermore, it will be generally aligned with thebottom face 30 of the device 20 when fully deployed. It otherembodiments, the patch contacting surface 70 may be configured so thatit is at another angle with respect to the frame member 60, and withrespect to the bottom face 30 of the device 20 when fully deployed.Other such angles are shown in FIGS. 5A, B depicting a portion ofdevices having alternative patch contacting surfaces. In one embodiment,it may be desirable for the patch contacting surface 70 to be aligned soas to form an angle of between 4 and 15 degrees with the plane of theframe member. In one aspect, the angle of the patch contacting surface70 may be selected so that it is aligned with the back of the a patchresting on retaining members 40 when the patch contacting surface 70contacts the patch. The impactor 62 can be formed of a polymer material.The handle 64 extends from the impactor 62, and can be integrally formedwith the impactor 62. The handle 64 is arranged to protrude through theslot 48 in the upper cover structure 26 of the housing 22, allowing theimpactor 62 position to be manipulated from outside the housing 22. Itshould be understood that FIG. 1 simply represents one configuration formanipulating the patch acceleration assembly 38. For example, a slot maybe provided on the upper cover portion 26, thereby allowing the handle64 or any other suitable actuation protrusion to protrude through theupper cover portion 26. Furthermore, the method for manipulating thepatch acceleration assembly 38 need not be by means of a directmechanical connection. For example, various linkages or gears may beprovided such that a button or knob on the exterior of the housing 22may be pressed or turned to manipulate the patch acceleration assembly38. In a further example, the patch acceleration assembly 38 may bemoved by a motor or solenoid that is electrically controlled by a buttonor knob on the exterior of the housing 22.

The torsion spring 68 biases the frame 60 of the patch accelerationassembly 38 relative to the base 24 of the housing 22. The torsionspring 68 can be a conventional coiled spring steel torsion spring. Bydefault, the torsion spring 68 biases the frame 60, and therefore alsothe impactor 62, toward the opening 32 in the base 24 of the housing 22.In a substantially de-energized state, the impactor is at rest andpositioned near the opening 32 in the base 24 of the housing 22. Bymoving the handle 64 to position the impactor 62 away from the opening,along an arcuate path that can be defined by movement of the handle 64along the slot 48 in the upper cover structure 26 of the housing 22, anoperator can store potential energy in the torsion spring 68. Energystored in the torsion spring 68 can be used to accelerate the impactor62 toward a patch and also to accelerate a patch that has contacted theimpactor 62. The amount of energy stored in the torsion spring 68 willvary depending on the amount of displacement of the impactor 62 awayfrom the opening 32 and along the arcuate path.

The appropriate torsion spring constant will depend upon a number ofparameters, including the mass of the patch acceleration assembly, themass of the patch, the arc length through which the patch accelerationassembly travels, and the desired speed of the patch on impact with asurface. The torsion spring constant will often be more than about 0.5Newton*mm/degree and sometimes more than about 2.0 Newton*mm/degree. Thetorsion spring constant will often be less than about 5.0Newton*mm/degree and sometimes less than about 4.0 Newton*mm/degree. Theimpactor 62 can be held at various points along the arcuate path eithermanually or, in some embodiments, with holding means (not shown) thatengage and temporarily secure the handle 64 along the slot 48 in theupper cover structure 26 of the housing 22. In further embodiments,demarcations or other indicators (e.g., a force readout display) can beprovided for indicating the levels of force associated with particulardegrees of displacement of the impactor 62 along the arcuate path.

The range of angular travel of the patch acceleration assembly willoften be less than about 170 degrees and sometimes less than about 110degrees. The range of angular travel of the patch acceleration assemblywill often be more than about 10 degrees and sometimes more than about60 degrees. The mass of the patch acceleration assembly will often bemore than about 1 gram and sometimes more than about 5 grams. The massof the patch acceleration assembly will often be less than about 100grams and sometimes less than about 30 grams.

FIG. 3 is a perspective view of a patch 72 (e.g., a patch 72 carrying amicroneedle array 74) mounted on the applicator device 20. The patch 72is disposed between the retainer members 40 and the bottom portion 44 ofthe recess 28 in the base 24 of the housing 22. The microneedle array 74faces away from the opening 32 in the base 24 of the housing 22. Thepatch 72, which may have adhesive surrounding the microneedle array 74on the surface facing away from the patch application device 20,contacts the upper surfaces 42 of the retainer members 40, but isgenerally not adhered firmly to the retainer members 40 due to therelease character of the upper surfaces 42. In a fully mounted position,as shown in FIG. 3, microneedle array carried on the patch 72 isgenerally aligned relative to the opening 32 in the base 24 of thehousing 22 (the opening 32 is not visible in FIG. 3).

The retainer members 40 have cutaway portions 76 that provide anenlarged, partially circular open region that is generally aligned withthe opening 32 on the bottom portion 44 of the recess 28 of the base 24of the housing 22. The wider, open region defined by the cutawayportions 76 facilitates patch application by reducing the amount ofdeflection of the patch 72 required during deployment to move the patch72 from a mounted position on the applicator device 20 to a targetlocation. Such cutaway portions 76 are optional and may be unnecessaryif, for example, the patch has a generally rectangular shape.

FIG. 4 is a partial cross-sectional view of a microneedle arraycartridge 80, having a patch 72 and a cover 82, mounted on theapplicator device 20. Mounting the patch 72 on the applicator device 20includes the following steps. The cartridge 80 is partially slid ontothe retainer members 40. Then the cartridge 80 is slid further along theretainer members 40, simultaneously separating the cover 82 from thepatch 72, until the patch 72 is fully mounted on the applicator device20 (e.g., such that the microneedle array 74 is aligned with the opening32 defined in the bottom portion 44 of the recess 28). The cover 82 isremoved from (i.e., separated from) the patch 72 to uncover and exposethe microneedle array 74 prior to microneedle deployment.

It should be recognized that the patch mounting structure shown in FIGS.3 and 4 is provided by way of example, and not limitation. In furtherembodiments, other means of mounting a patch on the applicator device 20can be used, and the design of the mounting structure is generallyindependent of the design of other components of the applicator device20. For instance, in further embodiments, one or more patches can bestored inside the housing 22 prior to application, and then dispensedfor application to a target site. The microneedle array 74 of the patch72 can be deployed as follows. An operator “loads” or “energizes” thepatch accelerating assembly 38 using the handle 64, to store potentialenergy in the torsion spring 68, by moving the impactor 62 and frame 60along the arcuate path. The operator can “load” the patch acceleratingassembly 38 either before or after the patch 72 is mounted to the device20. The amount of energy stored in the torsion spring 68 can be selectedbased on characteristics of the desired patch application site, and mayvary for different target sites, or may vary for different patches.Storing different amounts of energy in the torsion spring 68 permitsadjustment of an acceleration rate of a patch moved by the patchaccelerating assembly 38.

The applicator device 20 is also positioned against an applicationsurface, and the opening 32 is positioned relative to a target site forpatch delivery. Suitable sites for microneedle patch application on apatient's skin will vary, and the operator must select a suitableposition and orientation of the applicator device 20. When the patchaccelerating assembly 38 is energized, the patch 72 is fully mounted tothe applicator device 20, and the device 20 is positioned relative tothe target location, the operator then actuates the impactor 62 byreleasing the energy stored in the torsion spring 68, which moves theimpactor 62 toward the patch 72 along an arcuate path, which cancorrespond to the arcuate path defined by the slot 48 in the housing 22.The patch contacting surface 70 of the impactor 62 then contacts thepatch 72 to transfer energy to the patch 72 and accelerate it toward thetarget site. Release of the stored energy may be by any suitable means,such as by pressing a button or turning a knob to release a latch orother locking mechanism and thereby allowing the patch acceleratingassembly 38 to accelerate the patch 72 toward the target site. As shown,the arcuate path defined by the slot 48 is a portion (or arc) of acircle. It should be understood that in other embodiments the impactormay move along any type of arcuate (i.e., curved) path. Furthermore thepath may be substantially arcuate, that is, although predominatelycurved, there may be small portions of the path which are not curved.

In one embodiment (not shown), the patch may be directly affixed orotherwise releasably held by the patch acceleration assembly. Forexample, the patch may be releasably held to the impactor throughmagnetic attraction. The impactor may comprise a magnet and the patchmay comprise a metal capable of magnetic attraction. The impactor, forexample, may be a permanent magnet or an electromagnet and the patchbacking may comprise a metal that can be magnetically attracted. Forexample, a thin layer of ferrous foil may be incorporated into the patchbacking Such a magnetic attraction can allow the patch to be held to theimpactor until the patch contacts the skin. The adhesion between thepatch and the skin can then be sufficient to allow the patchacceleration assembly, and thus the applicator, to be removed from thepatch while allowing the patch to remain in place on the skin. Theadhesive force between the patch and the skin is typically more than themagnetic, attractive force between the patch and the impactor. In someinstances the adhesive force between patch and skin may be more thanabout twice as much as the magnetic, attractive force between patch andimpactor. The appropriate amount of magnetic interaction may be readilydetermined, and will depend on a number of factors, including themagnitude of the adhesive force between the patch and the skin, thedesign of the applicator and its method of removal from the patch oncethe patch is applied to the skin. Alternatively, the patch mayincorporate a magnet and the impactor can be made of a magneticmaterial, such as a steel leaf spring. Releasable magnetic attachmentmay be used with any of the hereinbefore or hereinafter describeembodiments, as well as with other embodiments of applicators, such asthose described in United States Patent Application Publication2002-0087182 and International Patent Publication WO05/123173, thedisclosures of which are herein incorporated by reference. Otherreleasable attachments, such as a weak adhesive bond, a snap-fitmechanism or a hook-and-loop attachment may also be suitable to connectpatch to impactor. In still another embodiment, the patch may bereleasably attached to a portion of the holding mechanism. For example,the impactor may be an elongated drive member, such as a leaf springhaving an opening or hole in its movable end. The patch may have a stubor other protrusion extending from its back surface that can be placedthrough the opening or hole in the leaf spring and gripped by theholding mechanism. The leaf spring will then also be held in place in acocked position, as it will be pinned between the patch and the holdingmechanism. Release of the patch from its attachment to the holdingmechanism and release of the leaf spring from its cocked position maythen occur simultaneously by activating the trigger. In one embodiment,a single use, disposable unit may be provided with the patchaccelerating assembly 38 already in an energized position, so that thedevice may be positioned and fired with the press of a button.

The patch 72 can be moved toward the target site along an at leastpartially arcuate path, such as when the patch 72 is moved in contactwith the impactor 62 as the impactor 62 moves along its arcuate path.The patch 72 could also move linearly toward the target site aftercontacting the impactor 62, such as where the impactor 62 momentarilycontacts the patch 72 and transfers its kinetic energy to the patch 72(which then travels along a generally linear path that differs from thearcuate path of the impactor 62). The deployed patch 72 can be adheredto the target site, as desired for delivery of molecules.

FIG. 6A is a perspective view of another embodiment of an applicatordevice 120 having a housing 122 that includes a base 124 and an uppercover structure 126. The device is elongate in shape and has a first,tapered end 127 and a second end 129. The second end 129 has a top andbottom sealed by a top peelable seal 131 having a tab 133 and a bottompeelable seal 132 having a tab 135 (only tab 135 is visible in FIG. 6A).FIG. 6B shows the applicator device after the peelable seals 131, 132have been removed. A trigger 137 is integrally formed in the top surfaceof the housing 122. The trigger is connected to the top surface of thehousing at a single attachment point 139, thus allowing the trigger tobe deflected downward by thumb or finger pressure as shown in FIG. 6D.

FIG. 6C is a cross-sectional view of the device showing a patch 172mounted on an impactor 170. The impactor 170 is integrally formed with adrive member 166 having a length extending from a fixed end 167 attachedto the housing 122 to a movable end 169. The drive member 166 isbendable along its length. A holding mechanism in the form of a latchuses a hook 125 attached to the housing 122. The hook 125 engages with aslot 171 in the movable end 169 of the drive member 166 to hold themovable end 169 of the drive member 166 away from the skin-contactingface 124 of the housing 122. The drive member may be any elongate,bendable member, such as, for example, a leaf spring. In use the deviceas shown in FIG. 6C is placed against a target surface, such as a skinsurface (not shown). Depression of the trigger 137, as shown in FIG. 6D,causes the hook 125 to pivot, thus releasing the movable end 169 of thedrive member 166 and allowing the drive member 166 to bias the patch 172towards the skin-contacting face 124. FIG. 6E shows the drive member 166fully deployed, having propelled the patch 172 past the skin-contactingface 124 so that the patch is pressed against the skin surface (notshown). FIG. 6F shows the device 120 being removed from the skin surface181, leaving a patch 172 with a microneedle array 174 in place on theskin surface 181. As shown, the impactor 170 is shown as a curled end ofa leaf spring, as this allows for a convenient means for providing aholding mechanism (via the slot 171 in the movable end 169 of the leafspring) while also providing a separate patch contacting and holdingsurface. However, any variety of suitable shapes may be used for themovable end 169 of the drive member 166, including a flat leaf springhaving no curled end.

FIG. 7A is a perspective top view of another embodiment of an applicatordevice 220 having a housing 222 that includes a base 224 and an uppercover structure 226. A trigger 237 extends from the upper coverstructure 226. FIG. 7B is perspective bottom view of the applicator 220showing a handle 249 and having retainers 240 for holding a microneedlepatch 272 with a microneedle array 274, similar to the patch retainingstructure shown in FIG. 3. FIG. 7C is a cross-sectional view showing animpactor 270 integrally formed with a drive member 266 having a lengthextending from a fixed end 267 attached to the housing 222 to a movableend 269. The drive member 266 is bendable along its length. A holdingmechanism in the form of a latch uses a hook 225 attached to the housing222. The hook 225 engages with a slot 271 in the movable end 269 of thedrive member 266 to hold the movable end 269 of the drive member 266away from the skin-contacting face 224 of the housing 222. A liftingmechanism 251 is shown in a raised position. The lifting mechanism 251is operably connected to the handle 249 (shown in dashed lines on theback side of the applicator) and is also configured so that it can liftthe drive member 266 into a position such as shown in FIG. 7C, where thedrive member 266 has been raised and latched onto hook 225. In use thedevice as shown in FIG. 7C is placed against a target surface, such as askin surface (not shown). After the drive member 266 is locked in placeby the holding mechanism, the handle 249 may be released, therebyreleasing the lifting mechanism 251 to a lowered position, such as shownin FIG. 7D. The trigger 237 may be pushed sideways, as shown in FIG. 7D,thus releasing the movable end 269 of the drive member 266 and allowingthe drive member 266 to bias the impactor 270 towards the patch 272 andthe skin-contacting face 224. As shown in FIG. 7D, the impactor 270drives the patch 272 from the retainers 240 and past the skin-contactingface 224 so that the patch is pressed against the skin surface (notshown). FIG. 7E shows the device 220 being removed from the skin surface281, leaving a patch 272 with a microneedle array 274 in place on theskin surface 281.

The applicator 220 may be used for applying multiple patches in thefollowing manner. After application of a patch, the handle 249 may belifted, thereby raising the lifting mechanism 251 and thus the drivemember 266 to a raised position, such as shown in FIG. 7C, and thetrigger 237 may be pushed back into place to lock the drive member 266in a raised position. The trigger 237 may be manually moved intoposition to lock the drive member 266. Alternatively, the trigger 237may be moved into position to lock the drive member 266 by a spring (notshown) that biases it towards the locked position or by a mechanism (notshown) connected to the handle 249 which causes the trigger 237 to moveto the locked position as the drive member 266 is raised by the handle.Any other suitable triggers and re-cocking mechanisms may be employed.Another patch may then be loaded into the retaining mechanism andapplied as described above.

The applicator device of the present invention may provide numerousbenefits and advantages. The housing may be shaped in a way thatgenerally resembles a mouse for a personal computer. This shape is lessthreatening to patients than applicators or other drug delivery devicesthat are shaped, for example, like a gun. The housing also providesadequate interior volume for protecting the patch accelerating assemblyand can optionally provide storage space for patches prior toapplication. Patch mounting may be quickly and easily accomplished,which is helpful for mass inoculations and other applications. It shouldbe understood, however, that any suitable housing shape may be used. Forexample, the housing may have a circular, square, or rectangularcross-section in some embodiments and may be a polyhedron in certainembodiments (i.e., the housing may define a volume formed by planefaces). In some embodiments the housing may be a polyhedron having oneor more rectangular faces, that is, a rectangular polyhedron. In someembodiments, the housing may have a flat or planar base with sides thatare continuously curved. It is preferred, but not necessary, that thepatch accelerating assembly is fully contained (with the exception ofthe handle) within the housing. In addition, a torsion spring or leafspring allows for simple and efficient adjustment of force used to applypatch with the applicator device, permitting the applicator device to beused in a variety of contexts and for patch application to a variety ofdesired patch sites. A method of applying a microneedle array using anapplication device of the present invention comprises mounting themicroneedle array on the microneedle array application device and movingthe microneedle array toward the target site along a substantiallyarcuate path. The array, for example, may be affixed to an impactorwithin the device, as described above. Release of the impactor allowsthe array to travel towards the target site along a substantiallyarcuate path.

Alternatively, a method of applying a microneedle array using anapplication device of the present invention comprises mounting themicroneedle array on the microneedle array application device and movingthe impactor along a substantially arcuate path to bring the microneedlearray into contact with the target site. For example, the array may bemounted within the application device using a retainer separate from theimpactor, such as shown in FIG. 3, and the impactor may be placed in aloaded position (i.e., where it contains stored energy) and thenreleased so as to travel along an arcuate path. The impactor will thencontact the microneedle array (or a patch holding the microneedle array)and bring the microneedle array into contact with the target site.

In still another alternative, a method of applying a microneedle arrayusing an application device of the present invention comprises placing amicroneedle patch on or adjacent to a target site. An application deviceof the present invention may be brought into alignment with themicroneedle array and triggered so as to cause the impactor to press themicroneedle array into the target site. The microneedle patch may beheld in place on a skin surface prior to contacting it with theapplication device by any suitable means, such as with use of acollapsible patch as described in International Patent PublicationWO2007/002523, the disclosure of which is herein incorporated byreference.

A method of applying a microneedle array using an application device ofthe present invention involves having the microneedle array reach adesired velocity that is effective to pierce the microneedles into theskin. The desired velocity is preferably controlled to limit or preventstimulation of the underlying nerve tissue. The maximum velocityachieved by the microneedle array upon impact with the skin is often 20meters per second (m/s) or less, potentially 15 m/s or less, andpossibly 10 m/s or less.

In some instances, the maximum velocity is 8 m/s or less. In otherinstances, the minimum velocity achieved by the microneedle array uponimpact with the skin is often 2 m/s or more, potentially 4 m/s or more,and possibly 6 m/s or more.

The mass of the portion of the device driving the microneedle array intothe skin is preferably light enough to avoid causing undue discomfort toa patient. In some instances, the mass of the impactor is less thanabout 6 grams, potentially less than about 4 grams, and possibly lessthan about 2 grams. The mass of the impactor is typically more thanabout 0.4 grams, potentially more than about 0.8 grams, and possiblygreater than about 1.2 gram. For purposes of determining the mass of theimpactor in embodiments where the impactor is integrally formed with thedrive member, such as shown in FIG. 6C, the impactor will generally beconsidered to include the portion above and behind the microneedlearray, but not to include the portion of the drive member extending awayfrom the movable end of the drive member and towards the fixed end ofthe drive member.

In one embodiment, the velocity achieved by the microneedle array uponimpact with the skin will be between about 4 m/s and 8 m/s, and the massof the impactor will be between about 0.4 grams and about 2 grams. Useof a leaf spring as a drive member directly coupled to a microneedlepatch may be particularly advantageous, as this allows the device toobtain desired velocities upon impact with the skin in combination witha relatively low mass impactor.

Such high-speed, low-mass delivery may be particularly advantageous whenapplying a microneedle array having a large number of microneedles.While not wishing to be bound by theory, it is believed that themomentum of an array having a large number of microneedles can be quitelow and still achieve acceptable penetration of the microneedles throughthe stratum corneum, because each microneedle has a very tiny mass andonly penetrates a relatively short distance into the skin. Inparticular, insertion of microneedle arrays having more than 100microneedles, often more than 500 microneedles, and occasionally morethan 1000 microneedles may be particularly effective when performedusing devices as described above.

The depth of penetration of the microneedles will vary depending on anumber of factors, such as the size and design of both the microneedlesand the microneedle array, as well as upon the velocity with which thearray impacts the skin. In one embodiment, the microneedles willpenetrate to a depth of more than 40 μm, sometimes more than 80 μm, andoccasionally more than 100 μm. In one embodiment, the microneedles willpenetrate to a depth of less than 300 μm, sometimes less than 200 μm,and occasionally less than 150 μm. In another embodiment, themicroneedles will penetrate to a depth that is more than 20% of the fullheight of the microneedle, sometimes more than 40%, and occasionallymore than 50%. In another embodiment, the microneedles will penetrate toa depth that is less than about 80% of the full height of themicroneedle, sometimes less than 60%, and occasionally less than 50%.

The microneedles are typically less than 500 microns in height, andsometimes less than 300 microns in height. The microneedles aretypically more than 20 microns in height, often more than 50 microns inheight, and sometimes more than microns in height. The height of themicroneedles may be measured as the distance that they protrude from aflat base or substrate. In one embodiment, the microneedles may protrudefrom an irregular substrate, for example, each microneedle may rest upona flat base or pedestal that itself protrudes from a planar substrate.

Because of the variability in the location of skin and the size ofdifferent individual's appendages, it is optional that the applicationdevice be designed such that the microneedle array travels at a velocityat or above the desired minimum velocities over a distance that issufficient to accommodate the variations in skin location and appendagesize relative to the application device. For example, the microneedlearray in the application device may move at or above the minimumvelocity over a distance of one millimeter or more. In some embodiments,the microneedle array may move at or above the minimum velocity over adistance of 5 millimeters or more. The microneedle arrays useful in thevarious embodiments of the invention may comprise any of a variety ofconfigurations, such as those described in the following patents andpatent applications, the disclosures of which are herein incorporated byreference. One embodiment for the microneedle arrays comprises thestructures disclosed in United States Patent Application Publication No.2003/0045837. The disclosed microstructures in the aforementioned patentapplication are in the form of microneedles having tapered structuresthat include at least one channel formed in the outside surface of eachmicroneedle. The microneedles may have bases that are elongated in onedirection. The channels in microneedles with elongated bases may extendfrom one of the ends of the elongated bases towards the tips of themicroneedles. The channels formed along the sides of the microneedlesmay optionally be terminated short of the tips of the microneedles. Themicroneedle arrays may also include conduit structures formed on thesurface of the substrate on which the microneedle array is located. Thechannels in the microneedles may be in fluid communication with theconduit structures. Another embodiment for the microneedle arrayscomprises the structures disclosed U.S. Patent Application PublicationNo. 2005/0261631, which describes microneedles having a truncatedtapered shape and a controlled aspect ratio. Still another embodimentfor the microneedle arrays comprises the structures disclosed in U.S.Pat. No. 6,091,975 (Daddona, et al.) which describes blade-likemicroprotrusions for piercing the skin. Still another embodiment for themicroneedle devices comprises the structures disclosed in U.S. Pat. No.6,312,212 (Sherman, et al.) which describes tapered structures having ahollow central channel. Still another embodiment for the micro arrayscomprises the structures disclosed in U.S. Pat. No. 6,379,324(Gartstein, et al.) which describes hollow microneedles having at leastone longitudinal blade at the top surface of tip of the microneedle.

Microneedle arrays and microneedle patches of the present invention maybe used to deliver drugs (including any pharmacological agent or agents)through the skin in a variation on transdermal delivery, or to the skinfor intradermal or topical treatment, such as vaccination.

In one aspect, drugs that are of a large molecular weight may bedelivered transdermally. Increasing molecular weight of a drug typicallycauses a decrease in unassisted transdermal delivery. Microneedle arraysof the present invention have utility for the delivery of largemolecules that are ordinarily difficult to deliver by passivetransdermal delivery. Examples of such large molecules include proteins,peptides, nucleotide sequences, monoclonal antibodies, DNA vaccines,polysaccharides, such as heparin, and antibiotics, such as ceftriaxone.In another aspect, microneedle arrays and microneedle patches of thepresent invention may have utility for enhancing or allowing transdermaldelivery of small molecules that are otherwise difficult or impossibleto deliver by passive transdermal delivery. Examples of such moleculesinclude salt forms; ionic molecules, such as bisphosphonates, preferablysodium alendronate or pamedronate; and molecules with physicochemicalproperties that are not conducive to passive transdermal delivery.

In another aspect, microneedle arrays and microneedle patches of thepresent invention may have utility for enhancing delivery of moleculesto the skin, such as in dermatological treatments, vaccine delivery, orin enhancing immune response of vaccine adjuvants.

Microneedle arrays and microneedle patches may be used for immediatedelivery, that is where they are applied and immediately removed fromthe application site, or they may be left in place for an extended time,which may range from a few minutes to as long as 1 week. In one aspect,an extended time of delivery may be from 1 to 30 minutes to allow formore complete delivery of a drug than can be obtained upon applicationand immediate removal. In another aspect, an extended time of deliverymay be from 4 hours to 1 week to provide for a sustained release ofdrug.

Although the present invention has been described with reference toseveral alternative embodiments, workers skilled in the art willrecognize that changes may be made in form and detail without departingfrom the spirit and scope of the invention.

1. An application device for applying a microneedle array comprising: ahousing having a skin-contacting face defining an opening that can bepositioned at a target site; an impactor for accelerating themicroneedle array toward the target site; and a drive member for biasingthe impactor relative to the housing; wherein the impactor is capable ofmoving along a substantially arcuate path to move the microneedle arraytoward the target site.
 2. The application device as claimed in claim 1,and further comprising a first retainer disposed along and spaced fromthe skin-contacting face of the housing and adjacent to the opening. 3.The application device as claimed in claim 2, wherein the first retainerhas a release surface.
 4. The application device as claimed in claim 1,wherein the drive member is capable of biasing the impactor towards thetarget site.
 5. The application device as claimed in claim 2, whereinthe first retainer has a release coating applied thereon.
 6. Theapplication device as claimed in claim 2, and further comprising asecond retainer disposed along and spaced from the skin-contacting faceof the housing and adjacent to the opening.
 7. The application device ofclaim 1, and further comprising a recess along the skin-contacting face,wherein the opening is disposed in the recess.
 8. The application deviceof claim 1, and further comprising an actuation protrusion connected tothe impactor for allowing an operator to manually position the impactoralong the substantially arcuate path.
 9. The application device of claim1, wherein the opening includes a wider portion for passage of amicroneedle array therethrough.
 10. The application device of claim 1,wherein an acceleration rate of the microneedle array toward the targetsite is adjustable.
 11. The application device of claim 1, wherein themicroneedle array moves along an at least partially arcuate path towardthe target site.
 12. The application device as claimed in claim 1wherein the drive member has a length extending from a fixed endattached to the housing to a movable end, wherein the drive member isbendable along its length and wherein the movable end of the drivemember is configured so as to be able to contact and propel themicroneedle array.
 13. The application device as claimed in claim 12wherein the movable end of the drive member serves as the impactor. 14.An application device for applying a microneedle array comprising: ahousing having a surface-contacting face with an opening; a drive memberhaving a length extending from a fixed end attached to the housing to amovable end, wherein the drive member is bendable along its length andwherein the movable end of the drive member is configured so as to beable to contact and propel the microneedle array.
 15. The applicationdevice as claimed in claim 12 and further comprising a holding mechanismfor holding the movable end of the drive member away from theskin-contacting face of the housing.
 16. The application device asclaimed in claim 15 and further comprising a trigger for releasing themovable end of the drive member from the holding mechanism.
 17. Theapplication device of claim 12 wherein the drive member comprises a leafspring.
 18. The application device of claim 12 wherein the microneedlearray is affixed to the movable end of the drive member.
 19. Theapplication device as claimed in claim 18 wherein the microneedle arrayis releasably affixed to the movable end of the drive member.
 20. Theapplication device of claim 1, and further comprising: a torsion springfor biasing the impactor relative to the housing.
 21. The applicationdevice as claimed in claim 20, wherein a first position and a secondposition are defined along the substantially arcuate path, and whereinpotential energy stored in the torsion spring when the impactor ispositioned relative to the first position differs from when the impactoris positioned relative to the second position.
 22. An application devicefor applying a microneedle array comprising: a housing having askin-contacting face defining an opening that can be positioned at atarget site; an impactor pivotally supported by the housing, theimpactor having an impacting portion, wherein the impacting portion iscapable of moving along a substantially arcuate path between a firstposition and a second position; and a torsion spring for biasing theimpactor relative to the housing.
 23. The application device as claimedin claim 22, and further comprising a first retainer disposed along andspaced from the skin-contacting face of the housing and adjacent to theopening.
 24. The application device as claimed in claim 23, wherein thefirst retainer has a release surface.
 25. The application device asclaimed in claim 24, wherein the release surface faces the housing.